1. Field of the Invention
The present invention relates generally to targets for treating Huntington's disease, and more specifically to methods and compositions for protecting cells from the toxicity of mutant Htt and treating Huntington's disease in an animal.
2. Description of the Related Art
Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disorder that is caused by the expansion of CAG repeats in exon 1 (HDx1) of huntingtin gene (Reddy et al. Trends Neurosci. 22:248-255 (1999)). The huntingtin gene is known and is the subject of U.S. Pat. No. 5,693,757, incorporated herein by reference. Expanded CAG repeats (40 and above), which form an abnormal polyglutamine (polyQ) stretch in the huntingtin (Htt) protein, result in a gain of toxic function and induce death in subpopulations of neurons in the striatum and cortex (Zoghbi et al. Annu. Rev. Neurosci. 23:217-247 (2000); Tobin et al. Trends Cell Biol. 10:531-536 (2000)). Neuronal death in HD has been attributed not only to polyQ toxicity, but also to activation of caspases, transcriptional dysregulation, and sequestration/inactivation of wild-type Htt and other important cellular factors. As disclosed below, the NF-κB pathway, which plays a central role in cell death and survival, is effected by mutant Htt.
NF-κB is sequestered in the cytoplasm by a family of inhibitory proteins (Iκ-Bs) (Ghosh et al., Annu Rev Immunol 16:225-260 (1998)). Iκ-Bs are phosphorylated by a signal-activated kinase complex known as I-κB kinase (IKK) (Ghosh and Karin, Cell [Suppl] 109:81-96 (2002)). This complex contains two catalytic subunits, IKKα and IKKβ, and a regulatory module, IKKγ (Karin and Lin, Nat Immunol 3:221-227 (2002)). Phosphorylated Iκ-Bs are ubiquitinated by an F-box E3-ligase, β-transducin repeat-containing protein (β-TrCP) (Spencer et al., Genes Dev 13:284-294 (1999) and subsequently degraded by proteosomes. Liberated NF-κB can bind DNA and promote gene expression (Pahl, Oncogene 18:6853-6866 (1999)).